Chemical manipulations of molecules containing sulfonic acid functional groups are not widespread, largely due to solubility and charge constraints of such molecules. For example, the scope of chemical reactions of molecules containing sulfonic acids is quite limited and must be carried out in very polar solvents such as water, dimethyl sulfoxide or dimethylformamide. Isolation of the final product can be difficult due to the polar nature of such molecules, which causes their solubility in these solvents to often be very high. In addition, many reagents frequently used in standard organic chemical synthesis require non-polar solvents in which compounds containing sulfonic acids generally do not dissolve.
Having a suitable protecting group for the sulfonic acid moiety would be of significant value in organic synthesis in allowing for a greater range of possible synthetic transformations, the ability to operate in typical non-aqueous organic solvents and a more general use of standard organic chemistry techniques. Present groups used for the protection of sulfonic acids have significant disadvantages. For example, sulfonamides derived from secondary amines, while readily prepared and stable to a variety of reaction conditions, typically require harsh conditions for hydrolysis which often cause modification of other functional groups in the molecule. Furthermore, isolation of the sulfonic acid from such hydrolysis mixtures is often difficult. Isopropyl sulfonate esters have also been used as sulfonic acid protecting groups, but are cleaved by iodide and boiling methanolid ammonia (Musicki and Widlanski, J. Org. Chem., 55:4231 (1990) and Tetrahedron Letters, 32:1267 (1991). Consequently, isopropyl sulfonate esters are incompatible with iodide reagents, for example in the Finkelstein reaction (March, Advanced Chemistry, 3rd edition, John Wiley and Sons, 1985), and with amine reagents, for example in forming Schiff bases. Sulfonic acids are also prevalent in molecules having various activities in vitro and in vivo including antiviral activities (such as anti-HIV, anti-HSV and anti-CMV activity). Compounds containing sulfonic acid groups with antiviral activities are disclosed in U.S. Ser. No. 08/156,443, U.S. Ser. No. 08/245,619 and "Compounds for Inhibiting HIV Infectivity" by Raymond J. Patch, John C. Roberts, Huai Gao and Peter V. Pallai (PRO94-03), filed concurrently in an application for a U.S. Patent, the teachings of which are hereby incorporated into this application by reference. Bioavailability can be improved if these ionized groups can be masked during passage through biological membranes. A method of decreasing the extent of ionization and increasing the lipophilicity of sulfonic acid functional groups is therefore needed to improve bioavailability in vivo.